PROJECT SUMMARY Despite chemotherapy, radiation and surgery, patients with undifferentiated pleomorphic sarcoma (UPS) frequently suffer incurable disease relapse. Immune checkpoint blockade is a promising new therapeutic approach for patients with UPS which promotes T cell mediated anti-tumor immunity. Still, the majority of patients do not benefit. Radiation therapy (RT), a cornerstone of preoperative treatment of UPS, can instigate T cell anti-tumor responses and synergize with immune checkpoint blockade. But RT can also result in the recruitment of immunosuppressive, pro-tumor myeloid cells that restrain anti-tumor T cell responses. This is particularly relevant in UPS, which is characterized by a brisk myeloid cell infiltrate. The candidate hypothesizes that reprogramming RT-induced myeloid cells toward an antigen-presenting, pro-inflammatory phenotype will promote T cell mediated anti-tumor immunity in UPS. To investigate the hypothesis the candidate proposes studies using BO-112, a synthetic nanoplexed version of poly I:C that activates double-stranded RNA sensing pathways, which are highly active in myeloid cells. These studies will be conducted in murine models of UPS (Aim 1) as well as in UPS patients (Aim 2). In Aim 1, the candidate will determine the impact of BO-112 on the fate, phenotype and immunomodulatory function of RT- induced myeloid cells. In Aim 2, the candidate evaluates the capacity of BO-112, RT, and anti-PD1 immune checkpoint blockade to remodel the myeloid compartment and instigate anti-tumor T cell responses in UPS patients enrolled on a window of opportunity phase 1 clinical trial. These studies will provide key insight into plasticity of RT-induced myeloid subsets, and their role in T cell mediated anti-tumor immunity, especially in response to BO-112. The candidate is an Assistant Professor in Radiation Oncology at UCLA specializing in the treatment of sarcoma. His scientific track record in tumor immunology and cancer immunotherapy highlights his commitment to an academic career in this field. The candidate's time is protected for research and career development (80% effort), and he has the space, equipment, personnel and resources necessary to complete the proposed studies. Along with his mentor, Dr. Antoni Ribas, and co-mentor, Dr. William McBride, the candidate has developed a comprehensive career development and training plan that will build expertise in four areas: (1) myeloid cell biology and plasticity, (2) genetic mouse models as tools to study sarcoma and the immune system, (3) analysis and interpretation of high-dimensional single cell phenotyping and transcriptomic data, and (4) conduct of a translational phase 1 clinical trial. These career development activities will support completion of the proposal and facilitate the transition to an independent scientific career conducting bench-to- bedside research, with an emphasis on leveraging translational immunology to transform the care of patients with sarcoma.